Affordable Access

Publisher Website

WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis.

  • Caetano da Silva, Caroline1
  • Edouard, Thomas2
  • Fradin, Melanie3
  • Aubert-Mucca, Marion2
  • Ricquebourg, Manon1
  • Raman, Ratish4
  • Salles, Jean Pierre2
  • Charon, Valérie5
  • Guggenbuhl, Pascal6
  • Muller, Marc4
  • Cohen-Solal, Martine1
  • Collet, Corinne1, 7
  • 1 INSERM U1132 and Université de Paris, Reference Centre for Rare Bone Diseases, Hospital Lariboisière, Paris F-75010, France. , (France)
  • 2 Endocrine Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Pediatric Clinical Research Unit, Children's Hospital, RESTORE INSERM U1301, Toulouse University Hospital, Toulouse 31300, France. , (France)
  • 3 Service de Génétique Clinique, Centre de Référence des Anomalies du Développement de l'Ouest, Hôpital Sud de Rennes, Rennes F-35033, France. , (France)
  • 4 Laboratory for Organogenesis and Regeneration (LOR), GIGA-Research, Liège University, Liège 4000, Belgium. , (Belgium)
  • 5 Department of Radiology, CHU de Rennes, Rennes F-35000, France. , (France)
  • 6 Department of Rheumatology, CHU de Rennes, Rennes F-35000, France. , (France)
  • 7 Département de Génétique, UF de Génétique Moléculaire, Hôpital Robert Debré, APHP, Paris F-75019, France. , (France)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
May 19, 2022
DOI: 10.1093/hmg/ddab349
PMID: 34875064


Monogenic early onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in Wnt family member 11 (WNT11) (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman, respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but Wnt family member 3A (WNT3A) recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2-LGR5 complex via the non-canonical Wnt pathway. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Report this publication


Seen <100 times